Structural Research of Outer Membrane Carboxylate Channels (Occ)
The bacterial outer membrane (OM) is relatively impermeable and only specific substrates can cross the channel proteins. This allows many bacteria to develop drug resistance. Outer membrane carboxylate channels (Occ) are specific channel proteins on the OM. This family requires a carboxyl group in the substrate to efficiently transport water-soluble small molecules. Structural studies of Occ and understanding the small molecule translocations facilitated by pore proteins at the molecular level are particularly important for drug discovery.
Research progress on Occ protein
Occ proteins are divided into two subfamilies. The OccK subfamily has 11 members (OccK1-11), which have specificity for positively charged amino acids. The OccD subfamily (OccD1-8), which contains 8 members, has more small pores and specificity for negatively charged aromatic acids. The crystal structure of this family is all monomers, consisting of 18 residues containing arginine and lysine β- Barrel composition. These residues protrude within the lumen to promote the permeation of carboxylate-containing substrates.
The structure and action mechanism of OccD1 (OprD)
The monophosphate-specific OccD1 (OprD) channel from Pseudomonas aeruginosa is trimeric. Its prominent structural feature is a trapezoid, which means that there is a row of arginine and lysine residues in the barrel wall used to bind the carboxylate ester groups of the substrate. During transportation, arginine binds to the carboxyl group near the center in the OccD1 pore and to the negatively charged side chain guanidine group formed by the Tyr side chain on the other side of the pore.
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Figure 1. The structure of two subfamily members of Occ. (Dai Y., 2021)
| Protein | Organism | Method | Resolution | PDB Entry ID |
| OccAB1 | Acinetobacter baumannii AB307-0294 | X-ray diffraction | 2.05 Å | 5DL5 |
| OccAB2 | Acinetobacter baumannii AB307-0294 | X-ray diffraction | 2.9 Å | 5DL6 |
| OccAB3 | Acinetobacter baumannii AB307-0294 | X-ray diffraction | 1.75 Å | 5DL7 |
| OccAB4 | Acinetobacter baumannii AB307-0294 | X-ray diffraction | 2.2 Å | 5DL8 |
| OccK1 (OpdK) | Pseudomonas aeruginosa | X-ray diffraction | 1.65Å | 3SYS |
| OccK2 (OpdF) | Pseudomonas aeruginosa | X-ray diffraction | 2.311Å | 3SZD |
| OccK3 (OpdO) | Pseudomonas aeruginosa | X-ray diffraction | 1.45Å | 3SZV |
| OccK4 (OpdL) | Pseudomonas aeruginosa | X-ray diffraction | 2.2 Å | 3T0S |
| OccK5 (OpdH) | Pseudomonas aeruginosa | X-ray diffraction | 2.6 Å | 3T20 |
| OccK6 (OpdQ) | Pseudomonas aeruginosa | X-ray diffraction | 2.4 Å | 3T24 |
| OccK7 (OpdD) | Pseudomonas aeruginosa PAO1 | X-ray diffraction | 3.166 Å | 4FRT |
| OccK8 (OprE) | Pseudomonas aeruginosa PAO1 | X-ray diffraction | 1.9 Å | 4FRX |
| OccK9 (OpdG) | Pseudomonas aeruginosa PAO1 | X-ray diffraction | 2.603Å | 4FT6 |
| OccK10 (OpdN) | Pseudomonas aeruginosa PAO1 | X-ray diffraction | 2.75Å | 4FSO |
| OccK11 (OpdR) | Pseudomonas aeruginosa PAO1 | X-ray diffraction | 2.323Å | 4FSP |
| OccD1 (OprD) | Pseudomonas aeruginosa | X-ray diffraction | 2.15 Å | 3SY7 |
| OccD2 (OpdC) | Pseudomonas aeruginosa | X-ray diffraction | 2.8 Å | 3SY9 |
| OccD3 (OpdP) | Pseudomonas aeruginosa | X-ray diffraction | 2.7 Å | 3SYB |
| OccK2 (OpdF) in complex with glucuronate | Pseudomonas aeruginosa PAO1 | X-ray diffraction | 2.45 Å | 4MFS |
| OccD1 (OprD) Y282R/D307H | Pseudomonas aeruginosa PAO1 | X-ray diffraction | 2.4 Å | 4FOZ |
Table 1. Structural research of outer membrane carboxylate channels (Occ).
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References
- Prajapati, J.D., et al. How to Enter a Bacterium: Bacterial Porins and the Permeation of Antibiotics. Chemical Reviews. 2021.121 (9):5158-5192.
- Eren E, et al. Toward understanding the outer membrane uptake of small molecules by Pseudomonas aeruginosa. J Biol Chem. 2013.288(17):12042-12053.
- Dai Y. Development of Computational Antibiotic Screening Platform Across Bacterial Outer Membrane Proteins. Syracuse University. 2021.
